Doxepin is a psychotropic agent with tricyclic antidepressant and anxiolytic properties, known under many brand-names such as Aponal®, the original preparation by Boehringer-Ingelheim, now part of the Roche group; Adapine®, Sinquan® and Sinequan® (Pfizer Inc.).

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It has antagonistic effects (blockade) on a variety of postsynaptic receptors:

Extremely strong : H1, H2

Strong : 5-HT2, Alpha1, Muscarinic

Moderate : 5-HT1

Weak : D2, Alpha2

These effects account for the actions as well for most side-effects (sedation, hypotension, anticholinergic side-effects, massive weight gain). Doxepin shows strong antagonism against the effects of Reserpin (amine depletion) in the animal model. Like other 'classical' antidepressants it has a sodium channel blocking activity, possibly accounting for its analgesic action. Additionally, Doxepin exerts a strong local-anesthetic action.

Human : Not exactly known, clinical experience indicates a rather high acute toxicity, as is the case with other tri-/tetracyclics. Fatal dose in sensitive adults may be as low as 500 to 1,000 mg oral (7 to 14 mg/kg). In children below 12 yrs. of age any oral intake is to be considered as serious.

chronic toxicity

Dog and Rat : Fat deposits in liver cells and decrease of triglyceride levels in plasma

Alleviation of the symptoms of alcohol and drug withdrawal (N.B.: Doxepin does not suppress seizure activity in alcoholics ('rum fits'). Cotreatment with benzodiazepines or barbiturates is needed to treat seizures effectively.

Gastrointestinal ulceration and other GI-problems (e.g. irritable bowel syndrome), whether part of depression or not. The action is due to strong H2-receptor antagonism. The efficiacy is comparable to H2-Receptor-Inhibitors.

MAO-Inhibitors of the irreversible type (tranylcypromine among others) : These drugs should normally be stopped at least 2 weeks before therapy with doxepin is started.

Children under 12 years of age should not be treated, because no sufficient clinical experience exists for this group of age.
Tricyclic antidepressant drugs, particularly when given in high doses, can induce sinus tachycardia, changes in conduction time and arrhythmias. A few instances of unexpected death have been reported in patients with cardiovascular disorders. Myocardial infarction and stroke have also been reported with drugs of this class. Therefore, doxepin should be administered with extreme caution to patients with a history of cardiovascular disease, those with circulatory lability and elderly patients. In such cases, treatment should be initiated with low doses with progressive increases only if required and tolerated, and the patients should be under close surveillance at all dosage levels.
Since tricylic agents are known to reduce the seizure threshold, doxepin should be used with caution in patients with a history of convulsive disorders. Concurrent administration of ECT and doxepin may be hazardous and, therefore, such treatment should be limited to patients for whom it is essential.
Close supervision is required when doxepin is given to hyperthyroid patients or those receiving thyroid medication because of the possibility of cardiovascular toxicity. At doses above 150 mg/day, it may block the antihypertensive effect of guanethidine and related compounds.

Before initiation of treatment a complete and differentiated blood count should be taken. If any value is pathologic, the blood count should be monitored closely under therapy with doxepin. If values are normal, blood counts should be taken during therapy in regular intervals (recommended: weekly during first month of therapy, monthly during the next 2 months, every 3 months afterwards).

If Doxepin is used chronically during pregnancy, the newborn may show a withdrawal syndrom with agitation, impaired cardio-respiratory functions, disturbed urination and defecation. Caution should be exerted in treating pregnant women on a regular basis.

Doxepin is found in significant amounts in the milk of lactating women. If therapy is necessary, lactation should be interrupted during treatment.

Patients with suicidal thoughts, or those with previous suicidal attempts, should be monitored closely under treatment with Doxepin. Perhaps, the decision is made to hospitalize high risk patients until remission or to prescribe an additional sedating drug like a benzodiazepine or chlorprothixene for 2-4 weeks of initial treatment with Doxepin (until significant remission). At least, the smallest amount of Doxepin should be prescribed at one time to minimize the risk of deliberate overdose.

Doxepin has an extremely low potential for abuse and psychological dependence (mostly noted with polytoxicomaniacs, possibly due to the strong anxiolytic action of Doxepin).

Withdrawal symptoms frequently seen when treatment with doxepin is stopped abruptly (agitation, anxiety, insomnia, sometimes activation of mania or rebound depression) are not indicative of addiction and can be avoided by reducing the daily dose of Doxepin gradually by approximately 25% each week. If treatment has to be stopped at once due to medical reasons, the use of a benzodiazepine (e.g. Lorazepam, Clonazepam, or Alprazolam) for a maximum of 4 weeks as needed will usually suppress withdrawal symptoms.

Doxepin may worsen psychotic conditions like schizophrenia and should be given with caution. The antipsychotic treatment should be continued.

With Zonalon® and Xepin; in most countries an external form (cream) is available for the treatment of itching skin disease; the effect is probably due to the affinity of doxepin for H1 and H2 receptors and action on muscarininc receptors.

Irreversible MAO-Inhibitors : agitation, delirium, coma, hyperpyrexia (high fever), seizures and severe changes in blood pressure. potentially fatal. N.B. Treatment-resistant hospitalized patients may be treated concomitantly with an MAO-inhibitor, if they are closely monitored by an expert and the initial dose of both drugs is low.

Depending on the disease to be treated, clinical condition, age, weight and liver function :

Initial doses may be as low as 5 mg in the evening for treatment of insomnia or as high as 100 mg oral as bedtime single dose or in divided doses in severely agitated depressive patients. Patients with severe opioid withdrawal symptoms often even require 3 times 50 mg or more in the first few days. Generally, initial doses should be low and increased step by step. Outpatients should not receive more than 150 mg daily. Hospitalized patients may receive up to 300 mg orally in divided doses. Up to 150 mg may be given as single bedtime dose. The dose for i.m.-injections and i.v.-infusions is usually 1/2 or less of the oral dose. Infusions should be given very slowly and the patient should lie during the infusion and for some hours afterwards in order to avoid severe postural hypotension.

It has been shown that Doxepin is able to decrease the risk of relapse of serious depression when given as longterm treatment after the remission is stable. If this applies for you, your physician will determine as well the daily dose and the duration of longterm treatment. The daily dose might be lower than the dose needed for full remission of your depression.

Doxepin was synthesized by Stach and Spingler from the German drug manufacturer C. F. Boehringer & Söhne GmbH in Mannheim. It was tested from 1963 to 1968 in different German and Swiss psychiatric institutions and was approved in Germany and elsewhere thereafter. The antidepressive effects were found to be excellent. Strong anxiolytic and sedative properties were also demonstrated. Doxepin has been in clinical use for several decades. The drug plays an important role in many indications today, not only in psychiatry/neurology.